1. Field of the Invention
The present application relates generally to huntingtin (Htt) proteolysis, methods for identifying compounds for protecting a cell from DNA damage-induced Htt proteolysis, methods and compositions for protecting cells from DNA damages, and methods and compositions for treating neurological disorders.
2. Description of the Related Art of Various Embodiments
The huntingtin gene is the subject of U.S. Pat. No. 5,693,757, incorporated herein by reference. Expanded CAG repeats (40 and above), which form an abnormal polyglutamine (polyQ) stretch in the huntingtin (Htt) protein, result in a gain of toxic function and induce death in subpopulations of neurons in the striatum and cortex (Zoghbi et al. Annu. Rev. Neurosci. 23:217-247 (2000); Tobin et al. Trends Cell Biol. 10:531-536 (2000)).
Generation of N-terminal fragments of mutant Htt is thought to initiate neurotoxicity, culminating in HD (Gafni et al. J. Biol. Chem. 279: 20211-20220 (2004); Graham et al. Cell 125:1179-1191 (2006); Ratovitski et al. Cell Cycle, 6:2970-2981 (2007). Wild type Htt is also cleaved and inactivated by proteases, and its deletion in the central nervous system (CNS) promotes neurodegeneration and is deleterious for development. However, the signaling pathways that regulate Htt proteolysis are poorly understood.